PROJECT SUMMARY Adolescence is a critical developmental period for tobacco initiation and progression to regular use and dependence. Comprehensive tobacco control policies that reduce the reinforcing effects of cigarettes in adolescents may decrease the number of cigarette experimenters who go on to become lifelong smokers. With the passage of the Family Smoking Prevention and Tobacco Control Act in 2009, the Food and Drug Administration (FDA) was granted the authority to establish standards for tobacco products as appropriate for the protection of public health, including the authority to mandate a reduction in the nicotine content of all cigarettes to minimally addictive levels. Numerous studies have found that adult smokers who are switched to very low nicotine content (VLNC) cigarettes experience reductions in smoking rates, nicotine intake, nicotine dependence and abstinence-induced craving relative to those who use normal nicotine content (NNC) cigarettes. However, to date, studies of VLNC cigarettes have excluded adolescent smokers, and are critically needed to inform potential product standards. Furthermore, as use of electronic cigarettes (e-cigarettes) has increased dramatically in adolescents, effects of VLNC cigarettes on smoking in youth must be examined in the context of e-cigarette availability. Project 3 is a 2 x 2 x 2 mixed-factors laboratory study in which a smoking choice procedure will be used to determine how the nicotine content of cigarettes and key characteristics of e- cigarettes (nicotine concentration and flavors) influence use of these products and their subjective effects in adolescents. In this single-site study, adolescents aged 15-19 (N=120), who are daily cigarette smokers and have used e-cigarettes on at least 5 occasions, will first complete a baseline session in which eligibility criteria are confirmed, background questionnaires are completed and participants gain experience with the e-cigarette device to be used in later sessions. Next, participants will complete 5 lab sessions in which NNC (15.8 mg/g) or VLNC (0.4 mg/g) cigarettes are available and e-cigarettes varying in nicotine concentration (2 mg/mL or 18 mg/mL) and flavor (tobacco or non-tobacco) are concurrently available. After sampling and rating the subjective effects of each product, participants will make a series of 10 choices between 2 puffs of either product or abstinence. An additional lab session during which e-cigarettes are not available will allow a direct comparison of the effects of NNC and VLNC cigarettes on smoking when no alternative product is available. We hypothesize that reducing the nicotine content of cigarettes will reduce cigarette choices and increase both e-cigarette choices and choices to abstain from either product. We further hypothesize that e-cigarettes with higher nicotine concentration and non-tobacco flavor will be most effective at reducing cigarette choices. We will also test the impact of these factors on the subjective effects of each product and explore whether the behavioral and subjective effects of each product vary as a function of age and gender. This project will provide the FDA with critically important information on how the nicotine content of combusted tobacco affects the reinforcing and subjective effects of cigarettes in adolescents, and how those effects are altered when e- cigarettes with different characteristics are available as alternatives.